tacrolimus and Burkitt-Lymphoma

Topics: Abnormal Karyotype; Adult; Antigens, CD; Biomarkers, Tumor; Burkitt Lymphoma; Diagnosis, Differential; Humans; Immunosuppressive Agents; Lung Transplantation; Lymph Nodes; Male; Postoperative Complications; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; T-Lymphocyte Subsets; Tacrolimus

Post-transplant lymphoproliferative disorder is a severe complication in solid organ transplant recipients, which is highly associated with Epstein-Barr virus infection in pediatric patients and occasionally presents as Burkitt- or Burkitt-like lymphoma. The mammalian target of rapamycin (mTOR) pathway has been described as a possible antitumor target whose inhibition may influence lymphoma development and proliferation after pediatric transplantation. We treated Epstein-Barr virus positive (Raji and Daudi) and negative (Ramos) human Burkitt lymphoma derived cells with mTOR inhibitor everolimus alone and in combination with clinically relevant immunosuppressive calcineurin inhibitors (tacrolimus or cyclosporin A). Cell proliferation, toxicity, and mitochondrial metabolic activity were analyzed. The effect on mTOR Complex 1 downstream targets p70 S6 kinase, eukaryotic initiation factor 4G, and S6 ribosomal protein activation was also investigated. We observed that treatment with everolimus alone significantly decreased Burkitt lymphoma cell proliferation and mitochondrial metabolic activity. Everolimus in combination with cyclosporin A had a stronger suppressive effect in Epstein-Barr virus negative but not in Epstein-Barr virus positive cells. In contrast, tacrolimus completely abolished the everolimus-mediated suppressive effects. Moreover, we showed a significant decrease in activation of mTOR Complex 1 downstream targets after treatment with everolimus that was attenuated when combined with tacrolimus, but not with cyclosporin A. For the first time we showed the competitive effect between everolimus and tacrolimus when used as combination therapy on Burkitt lymphoma derived cells. Thus, according to our in vitro data, the combination of calcineurin inhibitor cyclosporin A with everolimus is preferred to the combination of tacrolimus and everolimus.

Topics: Antineoplastic Agents; Burkitt Lymphoma; Calcineurin; Cell Proliferation; Cell Survival; Cyclosporine; Drug Therapy, Combination; Epstein-Barr Virus Infections; Everolimus; Herpesvirus 4, Human; Humans; Immunosuppressive Agents; Mitochondria; Ribosomal Protein S6 Kinases, 70-kDa; Signal Transduction; Tacrolimus; TOR Serine-Threonine Kinases; Tumor Cells, Cultured

We describe the case of a boy who presented with abdominal Burkitt lymphoma; he had been regularly using tacrolimus ointment 0.1% for severe recurrent atopic dermatitis for 7 years immediately prior to developing cancer. We present his medical history and review the current knowledge regarding a link between topical tacrolimus and malignancy risk.

Topics: Administration, Cutaneous; Burkitt Lymphoma; Child; Dermatitis, Atopic; Diagnosis, Differential; Humans; Ileal Diseases; Ileal Neoplasms; Ileocecal Valve; Immunosuppressive Agents; Intussusception; Male; Tacrolimus; Tomography, X-Ray Computed

Cross-linking of the B cell antigen receptor (BCR) with an anti-IgM antibody has been shown to induce dramatic apoptosis in type I Burkitt's lymphoma (BL) cells. However, the apoptotic mechanism triggered via BCR remains unknown. Here we reports a mechanism of BCR ligation-induced apoptosis involving protein phosphatase calcineurin and its specific substrate, transcriptional factor NF-AT. In response to BCR cross-linking, endogenous calcineurin was rapidly activated, and this facilitated nuclear translocation of NF-ATc2, a subtype of NF-AT members. Interestingly, nuclear-imported NF-ATc2 functioned pro-apoptotically in BL cells. The effect of NF-ATc2 was efficiently blocked with FK506, which prevented its nuclear translocation through inactivation of calcineurin. In addition, TR3 induction during BCR cross-linking was reduced by FK506 and the VIVIT peptide, which is a highly selective inhibitor for NF-AT. This strongly suggests that activation of NF-ATc2 by calcineurin is essential for TR3 recruitment, and that TR3 can be considered as a candidate for death effector in BCR-mediated apoptosis. Therefore, NF-ATc2 plays a crucial role in BCR-mediated apoptosis in type IBL, providing greater insight into unique BL characteristics through BCR signaling.

Topics: Apoptosis; Burkitt Lymphoma; Calcineurin; Calcium; Calcium Signaling; DNA-Binding Proteins; Gene Expression Regulation; Humans; Immunoglobulin M; Immunosuppressive Agents; NFATC Transcription Factors; Nuclear Proteins; Nuclear Receptor Subfamily 4, Group A, Member 1; Receptors, Antigen, B-Cell; Receptors, Steroid; Receptors, Thyroid Hormone; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Signal Transduction; Tacrolimus; Transcription Factors; Tumor Cells, Cultured

IL-2 gene transcription in T cells requires both TCR and costimulatory signals. IL-2 promoter activation in Jurkat T cells stimulated with superantigen presented by Raji B cells requires CD28 activation. The addition of rCTLA4Ig, which blocks CD28 binding to its ligand, to the cultures decreased IL-2 promoter activation by >80%. Interestingly, CTLA4Ig did not significantly inhibit the activation of either NF of activated T cells (NFAT) or AP-1 reporters. Therefore, activation of NFAT and AP-1 is insufficient for IL-2 promoter activation. In contrast, an RE/AP reporter was blocked by CTLA4Ig by >90%. Thus, the requirement for CD28 in IL-2 promoter activation appears to be due to RE/AP and not the NFAT or AP-1 sites. In addition, these data suggest that transcriptional activation of RE/AP is not mediated by NFAT, because activation of a NFAT reporter is not affected by the addition of CTLA4Ig.

Topics: Abatacept; Antigens, Bacterial; Antigens, CD; Antigens, Differentiation; B-Lymphocytes; Burkitt Lymphoma; CD28 Antigens; Cells, Cultured; CTLA-4 Antigen; DNA-Binding Proteins; Enterotoxins; Gene Expression Regulation; Genes, Reporter; Humans; Immunoconjugates; Interleukin-2; Jurkat Cells; Luciferases; Lymphocyte Activation; Lymphocyte Cooperation; Lymphocytes; NFATC Transcription Factors; Nuclear Proteins; Promoter Regions, Genetic; Recombinant Fusion Proteins; Regulatory Sequences, Nucleic Acid; Superantigens; T-Lymphocytes; Tacrolimus; Transcription Factor AP-1; Transcription Factors; Transcription, Genetic; Tumor Cells, Cultured

A new lymphoma cell line, designated SUBL, was established from a Japanese patient with Epstein-Barr virus (EBV)-associated lymphoma, which developed during FK 506 therapy after liver transplantation. This cell line has undergone 80 passages over a period of 22 months. The cultured cells were positive for CD19, CD20, CD21, CD22, CD23, and HLA-DR, and negative for CD10 and surface immunoglobulins. Immunoglobulin gene analysis revealed rearrangements of JH and JK. T-cell antigens or T-cell receptor gene rearrangements were not observed on the cell line. The SUBL cells were positive for Epstein-Barr virus nuclear antigen (EBNA). The EBV genome was detected in the original tissue and the cell line by the in situ hybridization method. These data indicate that this cell line represents the B-cell lineage at a pre-B-cell stage. SUBL cells showed successful heterotransplantation to mice with severe combined immunodeficiency (SCID). Chromosomal analysis revealed the karyotype 46,XY,t(2;3)(p11;q27). Molecular studies showed that c-myc, N-myc, and bcl-2 were not rearranged. This cell line will provide a useful in vitro system to study the relationship between chromosomal abnormalities and the activation of cellular oncogenes.

Topics: Animals; Antigens, CD; Antigens, Viral, Tumor; Burkitt Lymphoma; Cell Transformation, Viral; Child; Chromosomes, Human, Pair 2; Chromosomes, Human, Pair 3; Gene Rearrangement; Herpesvirus 4, Human; Humans; Immunophenotyping; In Situ Hybridization; Liver Transplantation; Lymphoma, B-Cell; Male; Mice; Mice, SCID; Neoplasm Transplantation; Pleural Effusion; Sigmoid Neoplasms; Tacrolimus; Translocation, Genetic; Tumor Cells, Cultured